Abstract Immune cells express receptors for the amino acid gamma-amino-butyric acid (GABA). Treatment with GABA can inhibit inflammation, prevent and reverse type 1 diabetes (T1D) and rheumatoid arthritis in animal models. It was recently shown that activation of GABA receptors can also promote replication of the insulin-producing -cells of the pancreas. Thus, activation of GABA receptors can inhibit inflammation and autoimmunity, as well as increase -cell mass, which are key goals for treating T1D and T2D. GABA itself, however, may be a suboptimal drug due to its relatively low affinity for its receptors and short half-life. Accordingly, repurposing higher-affinity longer-lived GABA receptor agonists is an attractive proposition. Although a number of such drugs are in clinical use, almost all of them were selected for their ability to pass through the blood-brain barrier and modulate GABA receptors on CNS neurons to treat neurological disorders such as epilepsy, seizures, and anxiety. Lesogaberan was developed by AstraZeneca as a peripherally-restricted GABA B-type receptor- specific agonist for the treatment of gastroesophageal reflux disease (GERD). Lesogaberan was found to be safe in several phase IIb clinical trials, but its beneficial effects for GERD were deemed to be insufficient. Because lesogaberan has a limited ability to pass through the blood-brain barrier it circumvents CNS side effects, making it an excellent candidate for repurposing for diabetes treatment. In this proposal we will test the hypothesis that lesogaberan monotherapy, and to a greater degree lesogaberan in combination therapy, can lead to durable disease remission after the onset of T1D in diabetes- prone NOD mice. First, we will examine the ability of lesogaberan over a dose range to reverse hyperglycemia in newly diabetic NOD mice. Second, we test whether lesogaberan treatment in combination with other promising T1D interventive therapies have an enhanced ability to reverse diabetes, and can provide effective therapy using lower dosage lesogaberan. Third, we will examine the ability of lesogaberan-based therapy to promote -cell replication and mass. We anticipate that our studies will provide preclinical proof-of-principle that lesogaberan can be repurposed for treating T1D, potentially leading to rapid translation into clinical trials with T1D patients.